While the roles of cysteine as an antioxidant and in cell signaling are widely appreciated, only recently has it been recognized that methionine, like cysteine, functions as an antioxidant and as a key component of a system for regulation of cellular metabolism. The efficiency of methionine as an antioxidant or as a component of signaling systems depends on its ready interconversion between the reduced form (methionine) and the oxidized form (methionine sulfoxide). Methionine sulfoxide reductase catalyzes the reduction of methionine sulfoxide back to methionine. The major focus of our research in the last year continues to be the identification of proteins that interact with methionine sulfoxide reductase A in vivo. Our concerted effort with a variety of techniques has yielded candidate interacting proteins, although we have not yet validated that they are true interacting proteins. Because of the importance of this issue, it will continue to be the focus of our research in the next reporting year. We have also created a knock-in mouse that expresses calmodulin mutated from methionine to glutamine at position 77. This was done because methionine sulfoxide reductase A stereospeifically oxidizes methionine 77, and glutamine is an analogue of methionine sulfoxide. We are now characterizing the phenotype of the mouse, especially its cardiovascular and neurobehavioral phenotypes. Another major focus is to elucidate the mechanism by which alpha-synuclein forms covalent oligomers. Our on-going collaboration with the laboratory of Ad Bax continues to increase our understanding of the novel derivatives that arise from the interaction of DOPAL with lysine residues in alpha-synuclein. Our current emphasis is to develop specific assays to detect and quantitate these novel derivatives in vivo.